We recently discovered that RGS14 is a novel suppressor of both synaptic plasticity/LTP in CA2 hippocampal neurons and hippocampal-based learning and memory. These studies are the first to implicate this gene/protein (RGS14) and this hippocampal region (CA2) in synaptic plasticity relating to learning and memory. Very little is known about the enigmatic CA2 region of brain, the resident genes there, or the underlying molecular mechanism(s) by which RGS14 regulates LTP there. We have found that RGS14 is a multifunctional scaffolding protein that integrates G protein and H-Ras/Raf/ERK signaling to inhibit certain forms of growth factor-directed MAP kinase signaling. RGS14 contains specific domains that bind active Gi/o1-GTP (RGS domain), inactive Gi11/2-GDP (GPR/GL domain) and active H-Ras/Rap2 and Raf (tandem Ras binding domains, or RBD). Several other signaling proteins and pathways have been identified in CA2 neurons that modulate LTP there, and that also link to RGS14 binding partners (Gi/o-linked A1 adenosine receptors, EGF and FGF Tyr-kinase receptors linked to H-Ras/Raf/MAP kinase signaling). My working hypothesis is that RGS14 integrates key signaling pathways that are critical for regulating synaptic plasticity in hippocampal CA2 neurons. The goal for these studies will be to develop experimental tools and to identify (for future study) molecular signaling pathways that RGS14 interfaces with in CA2 neurons to modulate synaptic plasticity. The Specific Aims will be to: Aim 1: Develop novel lentiviral delivery systems that will allow us to rescue lost RGS14 function (inhibition of LTP) in CA2 neurons, and to test if expression of RGS14 in CA1 neurons suppresses synaptic plasticity there. Aim 2: Develop novel lentiviruses encoding targeted loss-of-function mutations of RGS14 that will determine the role of the different RGS14 signaling partners/pathways in the regulation of CA2 synaptic plasticity/LTP. Aim 3: Determine how RGS14 interacts with known signaling mechanisms that regulate LTP in CA2 neurons. IMPACT: These studies will generate new experimental tools that will determine which of the identified signal functions of RGS14 are most important for its actions in CA2 neurons, (thereby helping to direct future studies), and establish what known pathways in CA2 neurons RGS14 interacts with to regulate synaptic plasticity important for key human cognitive functions. PUBLIC HEALTH RELEVANCE: These studies will define novel molecular mechanisms that underlie normal physiological processes such as learning and memory and social behaviors that are altered in human disease states such as schizophrenia or the autism and bipolar spectrum of disorders.